Full anticoagulation dosing confers survival advantage in hospitalized COVID-19 patients

A full, therapeutic dosing of anticoagulation flops for reducing the incidence of overall combined outcomes in noncritically ill patients hospitalized with COVID-19 as compared with prophylactic dosing, although there is a signal of benefit for mortality and disease progression with the therapeutic dosing, as shown in the FREEDOM COVID trial presented at ACC.23/WCC.

The 30-day composite of all-cause mortality, requirement for ICU level-of-care, systemic thromboembolism, or ischaemic stroke occurred in 11.3 percent of patients in the combined therapeutic-dose groups and in 13.2 percent of patients in the prophylactic-dose group (hazard ratio [HR], 0.85, 95 percent confidence interval [CI], 0.69–1.04; p=0.11). [ACC.23/WCC, abstract 410-12]

However, significantly fewer patients on therapeutic-dose vs prophylactic-dose anticoagulation died (4.9 percent vs 7.0 percent; HR, 0.70, 95 percent CI, 0.52–0.93; p=0.01) or required endotracheal intubation (6.4 percent vs 8.4 percent; HR, 0.75, 95 percent CI, 0.58–0.98; p=0.03) within 30 days.

In terms of safety, the frequency of in-hospital major bleeding was low at 0.4 percent and 0.1 percent of patients in the therapeutic-dose and prophylactic-dose anticoagulation groups, respectively. None of the patients overall experienced major bleeds after discharge through 30-day follow-up. Finally, there were no significant between-group differences in organ support-free days or in days alive and out-of-hospital.

“Although our study did not reach its primary endpoint, it has shown that patients admitted to the hospital for COVID-19—who are not yet critically ill but who have early signs of lung damage caused by the virus—substantially benefit from a higher dose of blood-thinning medication to stop disease progression, prevent the need for lung intubation and prevent death, without a significant increase in the risk of bleeding,” according to Dr Valentin Fuster, the principal investigator of the study and  physician-in-chief of The Mount Sinai Hospital in New York City, New York, US.

The modified intention-to-treat analysis included 3,398 hospitalized patients (median age 53 years, 59.7 percent male) with confirmed COVID-19 not requiring ICU-level treatment, enrolled across 10 countries. ICU level-of-care was defined as 1) mechanical ventilation following endotracheal intubation; 2) use of bilevel positive airway pressure, continuous positive airway pressure, or high flow nasal cannula oxygen (>30 litres per minute) for respiratory support; or 3) use of intravenous vasopressors, inotropes, or mechanical circulatory support.

Fuster emphasized that some patients could be admitted or transferred to the ICU for observation without requiring “ICU level-of-care” as so-defined.

The patients were randomly assigned to receive prophylactic-dose enoxaparin (n=1,141; 40 mg once daily, or 30 mg once daily for patients with creatinine clearance <30 mL/min), therapeutic-dose enoxaparin (n=1,136; 1 mg/kg every 12 hours, or 1 mg/kg once daily for those with creatinine clearance <30 mL/min), or therapeutic-dose apixaban (n=1,121; 5 mg twice a day, or 2.5 mg every 12 hours for those with at least two of the following factors: age ≥80 years, weight ≤60 kg, or serum creatinine ≥1.5 mg/dL). Enoxaparin was administered subcutaneously, while apixaban was administered orally.

Therapeutic dosing benefitted select patients

In subgroup analyses, patients with radiologic evidence of acute respiratory distress syndrome who received therapeutic-dose vs prophylactic-dose anticoagulation were less likely to die (7.9 percent vs 12.3 percent; HR, 0.63, 95 percent CI, 0.45–0.89) or experience a primary endpoint event (18.1 percent vs 21.9 percent; HR, 0.82, 95 percent CI, 0.64–1.04).

“This finding suggests that patients who are hospitalized for COVID-19 and have early signs of lung damage who are not yet critically ill will substantially benefit from receiving a treatment-strength dose of a blood thinner to stop disease progression in the lungs and prevent the need for a breathing tube,” said study co-author Dr Gregg Stone, professor of medicine (cardiology) at the Icahn School of Medicine at Mount Sinai.

“For patients already critically ill with COVID-19 and on a breathing tube, the use of a treatment-strength blood thinner is unlikely to be beneficial, but for patients with less advanced lung damage or other high-risk features, this treatment may be lifesaving,” Stone added.

Indeed, therapeutic dosing did not seem to be particularly beneficial in hospitalized, critically ill-patients with COVID-19 in the REMAP-CAP, ACTIV-4a, and ATTACC trials, even leading to a higher incidence of major bleed as compared with usual-care thromboprophylaxis. On the other hand, the dosing strategy helped reduce the number of days without organ support in noncritically ill patients hospitalized with COVID-19. As such, therapeutic-dose anticoagulation is currently not recommended for routine management of critically ill hospitalized patients with COVID-19.  [N Engl J Med 2021;385:777-789; N Engl J Med 2021;385:790-802; https://www.covid19treatmentguidelines.nih.gov/therapies/antithrombotic-therapy]

Fuster and Stone, along with their colleagues, pointed to the lower-than-anticipated primary events in FREEDOM COVID, mostly because of the low event rate from India, as the possible reason behind the discordance in the statistical significance between the primary composite endpoint (numerically but nonsignificantly lower with therapeutic-dose anticoagulation) and death and intubation (both significantly reduced).

“These results emphasize that varying country-specific thresholds for hospitalization may affect patient prognosis and the potential utility of advanced therapies,” Fuster said.

The investigators said that they would continue to follow patients up to 90 days after their enrolment in the trial and conduct additional preplanned subgroup analyses.